Progress in Drug Development Reviewed at The ALS Association Drug Company Working Group Meeting

May 5, 2015

News about a new drug, a new delivery method, a new trial, and a new approach to working with the Food and Drug Administration (FDA) were the highlights of The ALS Association’s annual Drug Company Working Group meeting, held in April in Washington, D.C., in conjunction with the American Academy of Neurology (AAN) Meeting.

“This meeting is an important opportunity for those working in ALS drug development, and those who are interested in getting into the field, to learn about progress and share new approaches,” said Lucie Bruijn, Ph.D., M.B.A., Chief Scientist for The ALS Association.

iPS Cells Uncover Potential Benefit of Epilepsy DrugKevin Eggan, Ph.D., of Harvard University, explained how induced pluripotent stem cells (iPS cells) have been used as a drug discovery tool, leading to an upcoming clinical trial that will test a drug shown to be effective in cells derived from people with ALS. The drug, called Retigabine, is an FDA-approved treatment for epilepsy. It reduces neuronal firing, “quieting” nerve cells to prevent them from harmful over-excitation.

Recent work has begun to focus on the potential importance of over-excitability of motor neurons in ALS, especially “upper” motor neurons, which run from the brain to the spinal cord. Dr. Eggan developed iPS cell lines from people with ALS to explore this phenomenon. In this technique, skin cells are chemically transformed into stem cells, which are then further treated to make them become motor neurons. In this way, they can be studied in the lab in large numbers.

Dr. Eggan’s study of over-excitability of ALS cells showed that Retigabine helped normalize the excessive firing of neurons in cell culture, and that this treatment improved the survival of these cells. The original experiment was done in cells from people with mutations in the SOD1 gene. “So we asked, ‘Is this also relevant to other types of ALS? This is where the value of iPS cell lines comes in,’” Dr. Eggan said, since the same testing protocol can be easily tried in each of the cell lines from different genetic form of the disease. Indeed, cells from each line displayed over-excitation, and Retigabine was beneficial in them all.

This has led to the development of a clinical trial that will soon commence at 12 study centers that are part of the Northeast ALS Consortium (NEALS) clinical trial network funded by The ALS Association. People with ALS will be enrolled to undergo a non-invasive procedure called transcranial electromagnetic stimulation, which induces a brief excitation of neurons in the brain. Subjects will receive either placebo or Retigabine, and the effect of treatment on excitation will be determined. If the drug helps reduce excitation in subjects in the trial, it may be considered for a longer-term trial, to determine if it can slow the disease.

Novel Drug Delivery System May Overcome Blood-brain BarrierSusan Rosenbaum, J.D., Founder and CEO of Lauren Sciences, described her company’s development of a novel drug delivery system. Many potentially beneficial drugs, including protein-based growth factors or DNA-based antisense molecules, cannot cross the blood-brain barrier. This means that they must be delivered directly to the central nervous system to have an effect. Such delivery is possible but is more invasive and risky than taking a drug either orally or intravenously. Dr. Rosenbaum’s company has developed a biologically based system that encapsulates such drugs and shuttles them across the blood-brain barrier, allowing peripheral administration for a drug that acts in the brain.

In technical terms, the system is a lipid-based spherical vesicle that encloses the drug within it. The lipids of the vesicle can be modified with a variety of “head groups,” or outer portions, which can be customized for different cell targets, such as motor neurons. “The vesicles cross the blood-brain barrier without disrupting it,” Dr. Rosenbaum noted.

The company is developing the system to deliver glial-derived neurotrophic factor (GDNF) in ALS, based on experiments showing that GDNF can promote survival of motor neurons. They have developed the necessary head groups for motor neuron targeting and selective release, she said, and are now working on encapsulating the GDNF in the vesicle. After that, they will look at efficacy of treatment in a mouse model. “Ultimately we hope to translate these into clinical studies,” Dr. Rosenbaum said.

Update on Upcoming Tirasemtiv TrialAndrew Wolff. M.D., Chief Medical Officer for Cytokinetics, gave the group an update on clinical trials of tirasemtiv. This drug increases muscle output at mid-levels of exertion, temporarily restoring some lost strength for everyday activities such as picking up an object. Results from early trials were promising, but the recently completed BENEFIT trial did not meet its major objective of showing a change in the ALS Functional Rating Scale score at the end of treatment. But there were improvements on a respiratory measure called slow vital capacity (SVC), which was encouraging. “We believe this is a clinically meaningful effect that warrants further study,” he said. With that in mind, a larger, Phase 3 trial is planned.

Dr. Wolff noted that several lessons from the BENEFIT trial are being used to shape the new trial, including better compensating for early dizziness—a common side effect—and a slower increase in dose, to increase tolerability. The double-blind trial will be 48 weeks in length and is projected to start in the second quarter of 2015. No enrollment information is available at this time, but The ALS Association will disseminate news about the trial as it emerges.

Developing an ALS-specific Guidance Document to Speed Clinical TrialsThe evening’s final presentation featured discussion about The Association’s initiative to develop an ALS-specific “guidance document” that would be submitted to the FDA. This initiative intends to bring together patients, caregivers, ALS advocacy groups, academics, and industry. It will be a consensus-based work product that incorporates stakeholder views in areas such as clinical trial design, biomarkers, surrogate endpoints, patient-reported outcomes, benefit-risk, natural history, diagnosis, public policy and others. The guidance will provide an ALS community-centered view of how the FDA should approach therapies for ALS with the aim of accelerating clinical trials, providing more clarity to industry, and ultimately delivering effective treatments to patients in a more timely fashion. The Association also will further engage both the FDA and NIH as part of this initiative such that the guidance initiative can have an impact on ALS drug development even before a final work product is submitted to the FDA. The project is the first ever patient focused guidance initiative for ALS drug development and is modeled after a similar effort recently conducted for Duchenne Muscular Dystrophy.

Working with the Muscular Dystrophy Association (MDA), The ALS Association in 2012 requested the FDA convene an ALS-specific hearing. The FDA did so, leading to a 2013 request from The ALS Association and MDA for development of a guidance document. However, the agency does not have the resources to develop such a guidance for every disease. Therefore, The ALS Association is utilizing resources made possible by last summer’s Ice Bucket Challenge to launch this critical initiative and bring together all stakeholders within the ALS community to move it forward. . The Association has set an ambitious timetable for a project of this magnitude and plans to submit a final work product to the FDA during the first quarter of 2016. During that time, the ALS community will have multiple opportunities to provide input and inform the development of the guidance.

“This groundbreaking effort should lead to faster trials, accelerate drug development and bring new treatments from the lab to patients as soon as possible” said Dr. Bruijn. “We are working with the entire ALS community, including other ALS organizations, industry, academia, government, and most importantly patients and caregivers. We are confident this effort will make a significant difference in the fight to find a treatment for ALS.”